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WO2016005527A1 - Méthode de traitement de troubles de la motricité par le befiradol - Google Patents

Méthode de traitement de troubles de la motricité par le befiradol Download PDF

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Publication number
WO2016005527A1
WO2016005527A1 PCT/EP2015/065763 EP2015065763W WO2016005527A1 WO 2016005527 A1 WO2016005527 A1 WO 2016005527A1 EP 2015065763 W EP2015065763 W EP 2015065763W WO 2016005527 A1 WO2016005527 A1 WO 2016005527A1
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WO
WIPO (PCT)
Prior art keywords
befiradol
pharmaceutically acceptable
acceptable derivative
sustained release
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2015/065763
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English (en)
Inventor
Bruno Paillard
Laurence DEL FRARI
Valérie BRUNNER
Adrian NEWMAN TANCREDI
Mark Varney
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pierre Fabre Medicament SA
Original Assignee
Pierre Fabre Medicament SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to PL15739213T priority Critical patent/PL3131549T3/pl
Priority to DK15739213.5T priority patent/DK3131549T3/en
Priority to KR1020167031277A priority patent/KR102533428B1/ko
Priority to JP2016567577A priority patent/JP6636458B2/ja
Priority to CA2946829A priority patent/CA2946829C/fr
Priority to AU2015286675A priority patent/AU2015286675B2/en
Priority to RU2016143875A priority patent/RU2702101C2/ru
Priority to EP15739213.5A priority patent/EP3131549B1/fr
Priority to MX2016014740A priority patent/MX374938B/es
Priority to US15/310,415 priority patent/US10548885B2/en
Priority to CN201580025182.0A priority patent/CN106456622B/zh
Priority to ES15739213.5T priority patent/ES2668379T3/es
Application filed by Pierre Fabre Medicament SA filed Critical Pierre Fabre Medicament SA
Priority to BR112016026648-0A priority patent/BR112016026648B1/pt
Publication of WO2016005527A1 publication Critical patent/WO2016005527A1/fr
Priority to ZA2016/07419A priority patent/ZA201607419B/en
Anticipated expiration legal-status Critical
Priority to US16/717,019 priority patent/US11090298B2/en
Priority to US17/359,182 priority patent/US12472169B2/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a method of treatment of movement disorders, comprising administering to a patient in need thereof an effective amount of befiradol, wherein the administering step provides an average patient's maximum plasma concentration of befiradol below about 15 ng/mL which occurs more than about 4 hours post administration, said method minimizing side effects of dizziness and nausea.
  • Sustained release pharmaceutical compositions that can be used according to this method are also described.
  • Movement disorders are conditions of the nervous system that affect the intentional ability to produce and control body movement, its speed, fluency, quality, and ease. They usually manifest as abnormal, involontary movements (dyskinesia) or postures (akinesia) such as chorea (involuntary, rapid, irregular, jerky movements), ballismus (involuntary movements similar to chorea but more violent, explosive), dystonia (involuntary sustained muscle spasms, usually producing twisting, repetitive movements or abnormal postures and positions), myoclonus (twitching or intermittent muscular spasms producing rapid, brief, movements), athetosis (repetitive involuntary, slow, sinuous, writhing movements, especially severe in the hands), akathisia (inability to sit still or remain motionless), ataxia (lack of coordination, often producing jerky movements), syncinesia (the occurrence simultaneously of both voluntary and involuntary movements), tics (involuntary muscle contractions that interrupt normal activities), bradykinesia (s
  • Parkinson's disease is caused by degeneration of nerve cells in the substantia nigra and is characterized by pronounced movement impairment, including bradykinesia, rigidity and/or tremor.
  • the quality of life of the patient is progressively decreased, particularly because of disturbed gait and balance. Falls and injuries are a common consequence of balance problems, and represent a threat to the health status and independence of the Parkinson's patient.
  • the symptomatic therapy of Parkinson's disease mainly consists in administering to the patient dopamine-replacing agents that alleviates motor symptoms and greatly improve the quality of life of patients.
  • Levodopa (3,4-hydroxyphenylalanine) which remains the gold standard for treatment of Parkinson's disease, acts as a dopamine prodrug, which is bio-metabolized into dopamine in the brain.
  • Dopamine in turn, activates dopamine receptors.
  • Direct-acting dopamine receptor agonists such as bromocriptine, lisuride, pramipexole, ropinirole and pergolide are also used mainly in the earlier stages of Parkinson's disease, but are less efficacious than levodopa in moderate to severe Parkinson's disease.
  • Parkinson's disease patients may cycle between "on” periods which are complicated by dyskinesia, and "off” periods in which they are severely parkinsonian, and experience profound disability despite the fact that the dopamine replacement remains an effective anti-Parkinson therapy, albeit at narrower and narrower doses, throughout the course of the disease.
  • Huntington's disease a rare, inherited disease that causes chronic progressive chorea and problems with movement coordination.
  • Huntington's disease slowing of movements, chorea, and occasional loss of balance are significant symptoms.
  • Other examples can be cited such as Tourette's syndrome (an inherited disorder characterized by multiple motor and vocal tics), dystonia (a disorder associated with slowness of movement, poor balance and difficulty moving around) and tardive dyskinesia (a disorder that can result from the use of a number of different pharmacological agents, such as antipsychotic drugs that target the dopamine system, and associated with facial tics and movements of the jaw, lips and tongue).
  • Tourette's syndrome an inherited disorder characterized by multiple motor and vocal tics
  • dystonia a disorder associated with slowness of movement, poor balance and difficulty moving around
  • tardive dyskinesia a disorder that can result from the use of a number of different pharmacological agents, such as antipsychotic drugs that target the dopamine system, and associated with facial tics and movements of the jaw,
  • agonists of the serotonin 5-hydroxytryptamine (5-HT) 1A receptor have been shown to ameliorate and / or prevent some aspects of movement disorders, such as extrapyramidal side effects associated with neuroleptics treatment, dyskinesia that arise from long-term Levodopa therapy in Parkinson's disease (Shimizu ef al. 2013 Aging and disease 4(1 ):1 -13) or involontary movement in Huntington's disease (Roppongi ei al 2007 Prog Neuropsychopharmacol Biol Psychiatry 31 (1 ):308-310).
  • Befiradol [(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4- ⁇ [(5-methyl-pyridin-2-ylmethyl)-amino]- methyl ⁇ piperidin-1 -yl]methanone] is a selective and high efficacy serotonin 5-HT1A receptor agonist (Colpaert ei al. 2002 Neuropharmacology 43 : 945-958), discovered by Pierre Fabre Laboratories (US 6,020,345; US 7,208,603).
  • the structural formula of befiradol is shown below:
  • Befiradol is intended to be of benefit for the treatment of Levodopa-induced dyskinesia and other movement disorders.
  • its use to treat patients suffering from movements disorders could be very limited because of its potential side-effects including dizziness and nausea.
  • these types of side effects are the most incapacitating in these patient populations because they already experience problems with balance, nausea and emesis, resulting from the movement disorder itself, the underlying pathology and/or the treatment they undergo, such as Levodopa or dopamine agonist administration.
  • the present invention relates to a method for treating a movement disorder in a patient in need thereof, comprising administering to the patient an effective amount of befiradol or a pharmaceutically acceptable derivative thereof, wherein the administering step provides an average patient's maximum plasma concentration of befiradol below about 15 ng/mL which occurs more than about 4 hours post administration, said method surprisingly minimizing side effects such as nausea and dizziness.
  • the effective amount according to the invention is, or is equivalent to, between 0.25 and 3 mg of befiradol base per day of treatment, preferably administered orally.
  • the movement disorder according to the invention is induced by the administration of one or several dopamine agonists and/or enhancers, preferably comprising levodopa.
  • the movement disorder according to the invention is dyskinesia induced by the administration of one or several dopamine agonists and/or enhancers, preferably comprising levodopa.
  • the patient according to the invention is affected by Parkinson's disease.
  • At least one sustained release pharmaceutical composition of befiradol or a pharmaceutically acceptable derivative thereof is administered in the method according to the invention, preferably orally.
  • the invention also relates to a sustained release pharmaceutical composition of befiradol or a pharmaceutically acceptable derivative thereof, comprising a pharmaceutically acceptable excipient that controls the release of befiradol, said composition delivering to a patient an effective amount of befiradol, wherein the average patient's maximum plasma concentration of befiradol is below about 15 ng/mL, and occurs more than about 4 hours post administration.
  • the sustained release pharmaceutical composition according to the invention comprises at least one pharmaceutically acceptable excipient that controls the release of befiradol, preferably a polymer, more preferably ethyl cellulose.
  • the sustained release pharmaceutical composition according to the invention comprises about 1 to about 20 %, preferably about 4 to about 20%, of ethyl cellulose by weight with respect to the total weight of the composition.
  • the sustained release pharmaceutical composition according to the invention comprises about 5 to about 20 %, preferably about 7 to about 20 %, of Surelease E-7- 19040TM by dry weight with respect to the total weight of the composition.
  • Figure 1 shows the mean plasma concentrations of befiradol versus time that were observed after a single oral administration of 1 mg of befiradol in four different formulations. Detailed in example 3. DETAILED DESCRIPTION OF THE INVENTION
  • a novel method of treatment of movement disorders comprising administering to a patient an effective amount of befiradol, and surprisingly minimizing side effects of dizziness and nausea, is provided herein.
  • befiradol or “befiradol base” refers to [(3- Chloro-4-fluoro-phenyl)-[4-fluoro-4- ⁇ [(5-methyl-pyridin-2-ylmethyl)-amino]-methyl ⁇ piperidin-1 - yl]methanone].
  • pharmaceutically acceptable refers to that which is useful in the preparation of a pharmaceutical composition that is generally safe, nontoxic and neither biologically or otherwise undesirable and that is acceptable for veterinary and human pharmaceutical use.
  • pharmaceutically acceptable derivative of befiradol includes any isotopic form, salt, solvate, ester, prodrug, or other precursor of befiradol which may be biologically metabolized into befiradol, or crystal form, which are pharmaceutically acceptable, as defined herein, and which have the desired pharmacological activity of befiradol.
  • Pharmaceutically acceptable salts of befiradol include the conventional nontoxic salts of befiradol such as those formed from pharmaceutically acceptable organic or inorganic acids or from pharmaceutically acceptable organic or inorganic bases.
  • salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid
  • organic acids such as acetic acid, trifluoroacetic acid, propionic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, glutamb acid, benzoic acid, salicylic acid, toluenesulfonic acid, methanesulfonic acid, stearic acid and lactic acid.
  • salts derived from inorganic bases such as soda, potash or calcium hydroxide and salts derived from organic bases such as lysine or arginine.
  • these salts may be synthesized from befiradol according to conventional chemical methods well known to the person skilled in the art.
  • said pharmaceutical acceptable derivative of befiradol is befiradol fumarate.
  • treating or “treatment” are used herein, unless otherwise indicated, to mean to relieve, alleviate, delay, reduce, reverse, improve, or prevent at least one symptom of a disease, disorder or condition. They may also mean to arrest, delay the onset and / or reduce the risk of developing or worsening a disease, disorder or condition.
  • the term "about” should be understood to mean within an acceptable error range for the particular value as determined by one skilled in the art, which will depend in part on how the value is measured or determined, i.e. the limitations of the measurement system.
  • “about” can mean within 1 or more than 1 standard deviation, per the practice in the art.
  • “about” can mean a range of up to 25%, preferably up to 20%, more preferably up to 10%, more preferably up to 5%, and more preferably still up to 1 % of a given value.
  • dopamine refers to [4-(2-aminoethyl)benzene- 1 ,2-diol].
  • levodopa refers to [3,4-dihydroxyphenylalanine].
  • the present invention concerns a method for treating a movement disorder in a patient in need thereof, comprising administering to the patient an effective amount of befiradol or a pharmaceutically acceptable derivative thereof, wherein the administering step provides an average patient's maximum plasma concentration of befiradol below about 15 ng/mL, which occurs more than about 4 hours post administration, said method minimizing side effects of dizziness and nausea.
  • the present invention thus also concerns befiradol or a pharmaceutically acceptable derivative thereof for its use in the treatment of a movement disorder in a patient in need thereof, characterized in that it comprises the administration to the patient of an effective amount of befiradol or a pharmaceutically acceptable derivative thereof, providing an average patient's maximum plasma concentration of befiradol or a pharmaceutically acceptable derivative thereof below about 15 ng/mL, which occurs more than about 4 hours post administration, the side effects of dizziness and nausea being minimized.
  • the present invention also concerns the use of befiradol or a pharmaceutically acceptable derivative thereof for the manufacture of a medbament for the treatment of a movement disorder in a patient in need thereof, characterized in that it comprises the administration to the patient of an effective amount of befiradol or a pharmaceutically acceptable derivative thereof, providing an average patient's maximum plasma concentration of befiradol or a pharmaceutically acceptable derivative thereof below about 15 ng/mL, which occurs more than about 4 hours post administration, the side effects of dizziness and nausea being minimized.
  • Said administering step is thus designed to produce a specifically low patient's maximum plasma concentration, but also a particular slow rate of increase of plasma concentration of befiradol by delaying the time at which the patient's maximum plasma concentration is attained, so as to minimize side effects of dizziness and nausea. This is notably manifested by a shallow gradient of patient's plasma concentration with respect to time post administration of befiradol, as illustrated, in a non limitative way, by the results of the clinical study detailed in example 3 and figure 1 .
  • said administering step provides an average patient's maximum plasma concentration of befiradol of about 5 ng/mL to about 15 ng/mL.
  • said administering step provides an average patient's maximum plasma concentration of befiradol below about 12 ng/mL.
  • said administering step provides an average patient's maximum plasma concentration of befiradol of about 5 ng/mL to about 12 ng/mL.
  • said patient's maximum plasma concentration of befiradol occurs between about 4 hours and about 12 hours post administration.
  • said patient's maximum plasma concentration of befiradol occurs more than about 5 hours post administration.
  • said patient's maximum plasma concentration of befiradol occurs between about 5 hours and about 12 hours post administration.
  • the maximal plasma concentration of befiradol and the time it occurs can be estimated from the concentration of befiradol quantified in plasma samples of the patient after administration.
  • the quantification of befiradol in plasma samples can be realized with any convenient validated analytical method as determined by those skilled in the art.
  • any convenient validated analytical method as determined by those skilled in the art.
  • a validated LC-MS/MS (liquid chromatography-tandem mass spectrometry) bioanalytical method preferably comprising preparing samples by solid phase extraction using ethyl acetate, drying, dissolving in a mixture of acetonitrile and ammonium acetate, performing a chromatographic separation in this liquid mobile phase and detecting by tandem mass spectrometry.
  • bioanalytical methods can be based on techniques such as HPLC (high performance liquid chromatography), GC (gas chromatography), UPLC (ultra performance liquid chromatography), supercritical fluid chromatography, mass spectrometry, nuclear magnetic resonance, electrophoresis, ligand binding assays (dual polarisation interferometry, ELISA - enzyme-linked immunosorbent assay, MIA - magnetic immunoassay, RIA - radioimmunoassay), LC-MS (liquid chromatography-mass spectrometry), GC-MS (gas chromatography-mass spectrometry), LC- DAD (liquid chromatography-diode array detection), CE-MS (capillary electrophoresis-mass spectrometry).
  • HPLC high performance liquid chromatography
  • GC gas chromatography
  • UPLC ultra performance liquid chromatography
  • supercritical fluid chromatography mass spectrometry
  • mass spectrometry nuclear magnetic resonance
  • electrophoresis
  • said administering step provides a plasma concentration of befiradol over time (AUC inf or total area under the befiradol plasma concentration-time curve) of about 30 hr.ng/mL to about 3000 hr.ng/mL, preferably of about 100 hr.ng/mL to about 1000 hr.ng/mL, preferably of about 300 hr.ng/mL to about 700 hr.ng/mL, more preferably of about 400 to about 500 hr.ng/mL.
  • AUC inf or total area under the befiradol plasma concentration-time curve of about 30 hr.ng/mL to about 3000 hr.ng/mL, preferably of about 100 hr.ng/mL to about 1000 hr.ng/mL, preferably of about 300 hr.ng/mL to about 700 hr.ng/mL, more preferably of about 400 to about 500 hr.ng/mL.
  • said administering step provides an average patient's maximum plasma concentration of befiradol below about 15 ng/mL (preferably below about 12 ng/mL), which occurs more than about 4 hours (preferably more than about 5 hours) post administration, and a plasma concentration of befiradol over time of about 30 hr.ng/mL to about 3000 hr.ng/mL (preferably of about 100 hr.ng/mL to about 1000 hr.ng/mL, preferably of about 300 hr.ng/mL to about 700 hr.ng/mL, preferably of about 400 to about 500 hr.ng/mL).
  • the term "patient” refers preferentially to a mammal, more preferentially to a human.
  • the patient according to the present invention is affected or very susceptible to being or likely to become affected by a movement disorder.
  • the patient according to the present invention is affected by Parkinson's disease.
  • the patient according to the present invention experiences one or several of the following disorders: balance disorders, coordination deficits, dizziness, emesis, nausea.
  • movement disorder refers to any condition that affects the movements of a patient, from any origin.
  • movement disorder can refer to a condition of the nervous system that affects the intentional ability to produce and/or control body movements or postures.
  • dyskinesia akinesia, bradykinesia, tardive dyskinesia, dopamine replacement therapy induced dyskinesia, levodopa induced dyskinesia, ataxia, akathisia, dystonia, essential tremor, myoclonus, chorea, ballismus, athetosis, tics.
  • the movement disorder according to the invention is associated with altered or impaired synaptic dopamine levels. In some embodiments, the movement disorder according to the invention is associated with a dysfunction of the basal ganglia.
  • the movement disorder according to the invention is selected from the group consisting of dyskinesia, chorea, ballismus, dystonia, athetosis, tics, myoclonus. In some preferred embodiments, the movement disorder according to the invention is dyskinesia. In the context of the present invention, movement disorders can also refer to a movement disorder associated with diseases such as, for example, Parkinson's disease, Huntington's disease, Tourette's syndrome, Rett syndrome, Wilson's disease, Machado-Joseph disease, restless leg syndrome.
  • diseases such as, for example, Parkinson's disease, Huntington's disease, Tourette's syndrome, Rett syndrome, Wilson's disease, Machado-Joseph disease, restless leg syndrome.
  • the movement disorder according to the invention is selected from those associated with Huntington's disease, Tourette's syndrome, or Parkinson's disease. In some preferred embodiments, the movement disorder according to the invention is associated with Parkinson's disease.
  • movement disorder can also refer to a movement disorder induced by the administration of one or more drugs, such as, for example, neuroleptics, antipsychotics (e.g. tardive dyskinesia), dopamine agonists and/or dopamine enhancers (e.g. levodopa).
  • dopamine agonist refers to a substance capable of binding to and activating one ore several dopamine receptors.
  • dopamine enhancer refers to a substance capable of enhancing the release or action of dopamine but which as no specific agonist activity at the dopamine receptors themselves.
  • dopamine precursors e.g. levodopa
  • drugs that prevent dopamine levels from decreasing such as inhibitors of monoamine oxidase (e.g.
  • the movement disorder according to the invention is induced by the administration of one or several dopamine agonists and/or enhancers, preferably comprising levodopa.
  • the movement disorder according to the invention is induced by the administration of levodopa.
  • the movement disorder according to the invention is tardive dyskinesia induced by neuroleptics and/or antipsychotics, or dyskinesia induced by dopamine agonists and/or enhancers, preferably comprising levodopa. In some preferred embodiments, the movement disorder according to the invention is dyskinesia induced by the administration of one or several dopamine agonists and/or enhancers, preferably comprising levodopa.
  • the movement disorder according to the invention is dyskinesia induced by the administration of one or several dopamine agonists and/or enhancers, preferably comprising levodopa; and the patient according to the invention is affected by Parkinson's disease.
  • the term "effective amount” refers to an amount or quantity of a compound which is effective in obtaining the desired therapeutic effect when administered to a patient. It will be appreciated that the precise therapeutic dose will depend on age, condition, weight, etc. of the patient, the route and method of administration, the nature of the condition, disease or disorder being treated and other factors.
  • the expression "equivalent to Section of befiradol base” refers, for a derivative of befiradol, to the corresponding amount of befiradol, if it was administered in its base form, as defined herein.
  • 0.65 mg of befiradol fumarate is equivalent to 0.5 mg to befiradol base.
  • the effective amount according to the invention is, or is equivalent to, between 0.001 and 1000 mg of befiradol base per day, preferentially between 0.01 and 100 mg of befiradol base per day, preferentially between 0.1 and 10 mg of befiradol base per day, preferentially between 0.25 and 5 mg of befiradol base per day, preferentially between 0.25 and 3 mg of befiradol base per day, preferentially between 0.5 and 2 mg of befiradol base per day, preferentially between 0.5 to 1 .5 mg of befiradol base per day, more preferentially 1 mg of befiradol base per day.
  • the effective amount according to the invention is, or is equivalent to, between 1 and 4 mg of befiradol base per day, preferentially between 1 .5 and 3 mg of befiradol base per day, more preferentially between 2 and 2.5 of befiradol base per day, or any one of these particular values, preferentially about 1 , 1 .5, 2, 2.5, 3, 3.5 or 4 mg of befiradol base per day.
  • the effective amount according to the present invention may be administered to a patient by various routes, e.g. orally, transdermally, perineurally or parenterally (e.g. by intravenous, subcutaneous, intraperitoneal, or intramuscular injection), among others, including buccal, nasal, ocular, pulmonary, sublingual, and rectal routes. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated and the nature of the condition to be treated. In some preferred embodiments, the effective amount according to the invention is administered orally in an appropriate formulation.
  • the movement disorder according to the invention is dyskinesia induced by the administration of one or several dopamine agonists and/or enhancers, preferably comprising levodopa; the patient according to the invention is affected by Parkinson's disease; and the effective amount according to the invention is, or is equivalent to, between 0.25 mg and 5 mg of befiradol base per day, preferentially between 0.25 and 3 mg of befiradol base per day, preferentially between 0.5 and 2 mg of befiradol base per day, preferentially between 0.5 to 1 .5 mg of befiradol base per day, more preferentially 1 mg of befiradol base per day.
  • the movement disorder according to the invention is dyskinesia induced by the administration of one or several dopamine agonists and/or enhancers, preferably comprising levodopa; the patient according to the invention is affected by Parkinson's disease; and the effective amount according to the invention is, or is equivalent to, between 1 and 4 mg of befiradol base per day, preferentially between 1.5 and 3 mg of befiradol base per day, more preferentially between 2 and 2.5 of befiradol base per day, or any one of these particular values, preferentially about 1 , 1 .5, 2, 2.5, 3, 3.5 or 4 mg of befiradol base per day .
  • the administration according to the present invention can be realized once a day or several times throughout the day, preferentially once a day or twice a day in equal doses.
  • the method according to the invention comprises administering to the patient at least one sustained release pharmaceutical composition of befiradol or a pharmaceutically acceptable derivative thereof.
  • composition refers to a composition comprising befiradol or a pharmaceutically acceptable derivative thereof and at least one pharmaceutically acceptable excipient.
  • the expression "pharmaceutically acceptable excipient” comprises any substance other than the active compound in a pharmaceutical composition, such as any diluent, additive, adjuvant or excipient.
  • any diluent, additive, adjuvant or excipient such as any diluent, additive, adjuvant or excipient.
  • sustained release refers to compositions that release befiradol (and optionally additional active ingredients) at a time other than promptly after administration, e.g., over an extended period of time that exceeds the duration of befiradol release from conventional immediate release compositions.
  • the composition according to the invention can comprise any effective amount of befiradol and/or one or more pharmaceutically acceptable derivatives thereof.
  • the composition according to the invention comprises between 0.001 and 1000 mg of befiradol and/or one or more pharmaceutically acceptable derivatives, expressed as equivalent amount of befiradol base, preferentially between 0.01 and 100 mg, preferentially between 0.1 and 10 mg, preferentially between 0.25 and 3 mg, preferentially between 0.5 and 2 mg, preferentially between 0.5 to 1 .5 mg, more preferentially 0.5 mg, more preferentially 1 mg.
  • composition according to the present invention may be administered to a patient by various routes, e.g. orally, transdermally, perineurally or parenterally (e.g. by intravenous, subcutaneous, intraperitoneal, or intramuscular injection), among others, including buccal, nasal, ocular, pulmonary, sublingual, and rectal routes.
  • routes e.g. orally, transdermally, perineurally or parenterally (e.g. by intravenous, subcutaneous, intraperitoneal, or intramuscular injection), among others, including buccal, nasal, ocular, pulmonary, sublingual, and rectal routes.
  • routes e.g. orally, transdermally, perineurally or parenterally (e.g. by intravenous, subcutaneous, intraperitoneal, or intramuscular injection), among others, including buccal, nasal, ocular, pulmonary, sublingual, and rectal routes.
  • buccal, nasal, ocular, pulmonary, sublingual, and rectal routes e.g. or
  • composition according to the present invention may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, hard and soft capsules, pills, lozenges, powders, granules, solutions, suspensions, emulsions, syrups, elixirs, suppositories, creams, ointments, lotions, gels, aerosols, patches, implants or the like, preferentially in one or more unit dosage forms suitable for simple administration of precise dosages.
  • the composition according to the invention takes the form of loaded capsules, preferentially hydroxypropyl cellulose or gelatin capsules.
  • composition according to the invention can comprise, depending on the intended mode of administration and the specific formulation, any suitable weight percentage of befiradol and/or one or more pharmaceutically acceptable derivatives thereof, with respect to the total weight of the composition.
  • the dosage form according to the invention comprises about 0.001 % to about 95% by weight of befiradol and/or one or more pharmaceutically acceptable derivatives thereof, with respect to the total weight of the composition, preferentially about 0.05% to about 50%, preferentially about 0.5% to about 25%, preferentially about 1 % to about 10%, preferentially about 1 % to about 5%, preferentially about 1 % to about 2.5%, with the remainder consisting essentially of pharmaceutically acceptable excipients.
  • the composition according to the present invention may further include other medicinal agents.
  • the composition according to the invention comprises an inert substrate, diluent or filler.
  • the composition according to the invention comprises an inert substrate that comprises sugar, more preferentially sugar spheres.
  • suitable inert substrates, diluents or fillers include, for example, isomalt, dicalcium phosphate dihydrate, calcium sulfate, lactose, mannitol, sorbitol, cellulose, microcrystalline cellulose, cyclodextrin, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized, starch, silicone dioxide, titanium oxide, magnesium aluminum silicate, or a mixture thereof.
  • the composition according to the invention can comprise sugar spheres in any suitable size.
  • the composition comprises sugar spheres having a size of about 100 to about 1000 ⁇ , preferentially about 200 to about 900 ⁇ , preferentially about 300 to about 800 ⁇ . preferentially about 400 to about 600 ⁇ , more preferentially about 500 to about 600 ⁇ .
  • the composition according to the invention can comprise any suitable amount of the inert substrate or filler (e.g. sugar spheres).
  • the composition according to the invention comprises about 15% to about 95% by weight of the inert substrate or filler, with respect to the total weight of the composition, preferentially about 50% to about 95%, preferentially about 75% to about 90%.
  • the stable dosage form may comprise about 75% to about 90% by weight of sugar spheres having a size of about 500 to about 600 ⁇ , with respect to the total weight of the composition.
  • the composition according to the invention also comprises a binder, preferentially hydroxypropylcellulose.
  • suitable binders include, for example, polyvinylpyrrolidone (e.g., Povidone K30), starch, polyvinyl alcohol, pre-gelatinized starch, gelatin, sucrose, glucose, dextrose, lactose, sorbitol, polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, hydroxypropylmethylcellulose, ethylcellulose, veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid, or a mixture thereof.
  • composition according to the invention can comprise any suitable amount of the binder (e.g., hydroxypropylcellulose).
  • the composition according to the invention comprises about 0.1 % to about 15% by weight of the binder, with respect to the total weight of the composition, preferentially about 1 % to about 10%, preferentially about 3% to about 6%.
  • the composition according to the invention also comprises an anti- adherent or lubricant, preferentially talc.
  • suitable anti-adherents or lubricants include, for example, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, mineral oil, sodium stearyl fumarate or mixtures thereof.
  • composition according to the invention can comprise any suitable amount of the lubricant or anti-adherent (e.g. talc).
  • the composition according to the invention comprises about 0.1 % to about 15% by weight of the lubricant or anti-adherent, with respect to the total weight of the composition, preferentially about 0.1 % to about 5%, preferentially about 0.1 % to about 1 %.
  • the controlled release of befiradol can be achieved by any pharmaceutically acceptable mean as determined by the person skilled in the art.
  • Diffusion systems Characterized by the release rate of drug, being dependent on its diffusion through an inert membrane barrier, usually an insoluble polymer.
  • Dissolution systems The release of drug is limited by the rate of dissolution of the system. Sustained-release compositions are made by decreasing their rate of dissolution. The approaches to achieve this decrease include preparing appropriate salts or derivatives, coating the drug with a slowly dissolving material, or incorporating it into a tablet with a slowly dissolving carrier.
  • Osmotic pressure is used to generate a constant release of drug, using a semi-permeable membrane that is permeable to water, but not to the drug.
  • Ion-exchange systems They generally use resins composed of water-insoluble cross- linked polymers. These polymers contain salt-forming functional groups in repeating positions on the polymer chain. The drug is bound to the resin and released by exchanging with appropriately charged ions in contact with the ion-exchange groups. The free drug diffuses out of the resin.
  • the drug-resin complex is prepared either by repeated exposure of the resin to the drug in a chromatography column, or by prolonged contact in solution.
  • Swelling and expansion systems Based on hydrogels which swell fast upon contact with water which lead to a large increase in size and a prolonged transit time in the stomach.
  • - Floating systems If the dosage form has a lower density than the gastric fluids, it will float on a top of the stomach content, allowing for an increased time span to release the drug.
  • Bioadhesive or mucoadhesive systems Based on bioadhesive or mucoadhesive polymers such as polyacrylic acid and chitosen to achieve the dosage forms sticking on to the mucosa.
  • Methods to produce controlled release systems useful for compositions of the present invention include, but are not limited to, crystallization, condensation, co-crystallization, precipitation, co- precipitation, emulsification, dispersion, high pressure homogenisation, encapsulation, spray drying, coacervation, phase separation, solvent evaporation to produce microspheres, extrusion and supercritical fluid processes.
  • the composition according to the invention comprises at least one pharmaceutically acceptable excipient that controls the release of befiradol.
  • Said excipient can be any controlling agent, polymeric agent or coating agent (e.g. ethyl cellulose).
  • Suitable release controlling agents include, for example, cellulose and cellulose derivative, wax, carbomer, polyalkylene polyol, polycarbophil, methacrylic acid derivative, gelatin, gum, polyethylene oxide, and polyvinyl pyrrolidone, or mixtures thereof.
  • said excipient is a polymer, either biodegradable or non-biodegradable; preferentially selected from the group consisting of ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers (preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate), and other methacrylic resins that are commercially available under the trade name EudragitTM (Evonik), including EudragitTM L30D-55 and LI00-55, EudragitTM, and EudragitTM NE,
  • composition according to the invention can comprise any suitable amount of said excipient that controls the release of befiradol (e.g. ethyl cellulose).
  • the composition according to the invention comprises about 1 % to about 30% by weight of the said excipient with respect to the total weight of the composition, preferentially about 1 % to about 25%, preferentially about 1 % to about 20%, preferentially about 2% to about 20%, preferentially about 4% to about 20%, preferentially about 4% to about 15 %, more preferentially about 8% to about 15%.
  • the composition according to the invention also comprises a plasticizer in some preferred embodiments, for example triglycerides, oleic acid, or a mixture thereof.
  • plasticizers include, for example, triethyl citrate, polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, tributyl citrate, triethyl acetyl citrate, glycerolmonostearate, castor oil, acetylated monoglycerides, or a mixture thereof.
  • the composition according to the invention can comprise any suitable amount of the plasticizer (e.g. mixture of oleic acid and triglycerides).
  • the composition according to the invention comprises about 0.1 % to 15% by weight of the plasticizer, with respect to the total weight of the composition, preferentially about 0.1 % to about 5%, preferentially about 1 % to about 5%.
  • Aqueous dispersions of ethyl cellulose, also comprising a plasticizer, are commercially available under the trade name SureleaseTM (Colorcon).
  • SureleaseTM Commercially available under the trade name SureleaseTM (Colorcon).
  • the formula of Surelease E-7-19040TM consists in purified water, ethyl cellulose 20mPa.s, ammonium hydroxide 28%, triglycerides medium-chain and oleic acid.
  • the composition according to the invention comprises an aqueous dispersion of ethyl cellulose, preferentially Surelease E-7-19040TM.
  • composition according to the invention can comprise any suitable amount of Surelease E-7- 19040TM.
  • the composition according to the invention comprises about 1 to about 30% by dry weight of Surelease E-7-19040TM, with respect to the total weight of the composition; preferentially about 2% to about 25%, preferentially about 5% to about 20%, preferentially about 7% to about 20%, preferentially about 7% to about 15%, about 9% to about 15%, preferentially about 9.88% or about 14.49%.
  • the composition according to the invention comprises about 1 % to about 5% by weight of befiradol and/or one or more pharmaceutically acceptable derivatives thereof; about 75% to about 90% by weight of an inert substrate or filler; about 3% to about 6% by weight of a binder; about 2% to about 20% by weight of an excipient that control the release, preferentially about 5% to about 20%, preferentially about 5% to about 15%, preferentially about 9% to about 15%; about 1 % to about 5% by weight of a plasticizer; and about 0.1 % to about 1 % by weight of an antiadherent or lubricant, with respect to the total weight of the composition.
  • the present invention has also as an object a sustained release pharmaceutical composition of befiradol or a pharmaceutically acceptable derivative thereof, comprising a pharmaceutically acceptable excipient that controls the release of befiradol, said composition delivering to a patient an effective amount of befiradol, wherein the average patient's maximum plasma concentration of befiradol is below about 15 ng/mL, and occurs more than about 4 hours post administration.
  • Hard Capsule shell composition (% w/w): Red iron oxide (0.47%), titanium dioxide (1 .0%), 5 yellow iron oxide (0.45%), gelatin (qsp 100%).
  • composition of Surelease E-7-19040 ® (provided by Colorcon): Purified water, ethyl cellulose 20mPa.s, ammonium hydroxide 28%, triglycerides medium-chain, oleic acid. 0
  • Example 3 Pharmacokinetics and tolerability of four compositions of befiradol clinical study Tested compositions:
  • IR (immediate release) composition 0.65 mg befiradol fumarate salt (equivalent to 0.50 mg befiradol) and excipients (calcium phosphate dibasic anhydrous, cellulose microcrystalline, silica 5 colloidal anhydrous and magnesium stearate) in sufficient quantitiy for one tablet
  • Hard Capsule shell composition (% w/w): Red iron oxide (0.47%), titanium dioxide (1 .0%), yellow iron oxide (0.45%), gelatin (qsp 100%).
  • the administration was a single, 1 mg (2 x 0.5 mg capsules or tablets) of befiradol, oral administration in the morning.
  • Blood samples for pharmacokinetic analyses were performed before morning drug administration (Time 0), then 0.5h, 0.75h, 1 h, 1 .5h, 2h, 3h, 4h, 5h, 6h, 7h, 9h, 12h, 24h, 48h, T72h, T96h, T120h, T144h after each befiradol administration.
  • Befiradol was quantified in plasma samples collected during the study using a validated LC- MS/MS (Liquid Chromatography with tadem Mass Spectrometry) bioanalytical method (see details hereafter).
  • T max time to reach the maximal plasma concentration
  • AUCi ast (observed area under the plasma concentration-time curve from zero to the last quantifiable point) was calculated according to linear-up / log-down trapezoidal rule.
  • AUCin f total area under the plasma concentration-time curve was estimated as the sum of two areas, AUCiast and AUCext (extrapolated area from the last quantifiable point to infinity; estimated as the ratio Clast Kel, where Clast is the observed concentration at Tlast and Kel is the terminal phase rate constant).
  • T 1 ⁇ 2 (experimental half-life) was calculated as In2/Kel, with Kel (terminal phase rate constant) estimated using the negative slope of the least square regression analysis of the log- concentration versus time data for the terminal linear position of the curve. Below limit of quantitation values occurring at the last time points were excluded from the analysis.
  • F re i (relative bioavailability, expressed as %, of each MR formulation versus the IR formulation) was calculated as follows:
  • the tolerability analysis was descriptive.
  • Plasma samples 500 ⁇ _ were prepared by solid phase extraction using 1 mL ChemElut® cartridges (VARIAN). Elution was performed using 2 x 3 ml., of ethyl acetate. The extracts were dried under nitrogen stream. The dry residue was then dissolved in mobile phase and injected into LC/MS-MS system .
  • the chromatographic separation was performed on a Chromolith Fast Gradient RP 18e, 50 x 2mm I.D. column using a mobile phase made of acetonitrile 1 15 mM ammonium acetate at pH 3 (20/80, v/v).
  • the samples were injected in the Turbo V ESI interface set at 600°C. Detection was achieved by tandem mass spectrometry and a dwell time of 700 ms.
  • the response was linear with concentration in the 0.1 - 100 ng .mL range for befiradol .
  • the methodology proved to be specific, accurate and precise.
  • the response versus concentration data was fitted by least-squares linear regression with 1 /X 2 weighting factor.
  • the limit of quantification was 0.1 ng.mL 1 for befiradol.
  • Each subject reported a 1 to 4-hour episode of mild dizziness, and one of these 5 subjects (IR formulation) also reported a headache and nausea.

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Abstract

La présente invention concerne une méthode de traitement des troubles de la motricité, comprenant l'administration au patient le nécessitant d'une quantité efficace de befiradol, l'étape d'administration conduisant chez le patient à une concentration plasmatique maximale de befiradol inférieure à 15 ng/mL en moyenne s'établissant plus de 4 heures après l'administration, ladite méthode rendant minimaux les effets secondaires de type vertige et nausée. L'invention concerne également des compositions pharmaceutiques à libération prolongée qui peuvent être utilisées selon cette méthode.
PCT/EP2015/065763 2014-07-09 2015-07-09 Méthode de traitement de troubles de la motricité par le befiradol Ceased WO2016005527A1 (fr)

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DK15739213.5T DK3131549T3 (en) 2014-07-09 2015-07-09 PROCEDURE FOR TREATING MOVEMENT DISORDERS WITH BEFIRADOL
KR1020167031277A KR102533428B1 (ko) 2014-07-09 2015-07-09 베피라돌을 이용한 이상운동질환 치료 방법
JP2016567577A JP6636458B2 (ja) 2014-07-09 2015-07-09 運動障害をベフィラドールで処置するための方法
CA2946829A CA2946829C (fr) 2014-07-09 2015-07-09 Methode de traitement de troubles de la motricite par le befiradol
AU2015286675A AU2015286675B2 (en) 2014-07-09 2015-07-09 A method for treating movement disorders with befiradol
RU2016143875A RU2702101C2 (ru) 2014-07-09 2015-07-09 Способ лечения двигательных расстройств бефирадолом
EP15739213.5A EP3131549B1 (fr) 2014-07-09 2015-07-09 Méthode de traitement de troubles de la motricité par le befiradol
US15/310,415 US10548885B2 (en) 2014-07-09 2015-07-09 Method for treating movement disorders with befiradol
MX2016014740A MX374938B (es) 2014-07-09 2015-07-09 Un método para el tratamiento de trastornos del movimiento con befiradol.
PL15739213T PL3131549T3 (pl) 2014-07-09 2015-07-09 Sposób leczenia zaburzeń ruchowych przy użyciu befiradolu
ES15739213.5T ES2668379T3 (es) 2014-07-09 2015-07-09 Método para el tratamiento de trastornos del movimiento con befiradol
CN201580025182.0A CN106456622B (zh) 2014-07-09 2015-07-09 用贝非拉醇治疗运动障碍的方法
BR112016026648-0A BR112016026648B1 (pt) 2014-07-09 2015-07-09 Befiradol ou um derivado farmaceuticamente aceitável do mesmo, composição farmacêutica de liberação sustentada e seus usos no tratamento de um distúrbio dos movimentos
ZA2016/07419A ZA201607419B (en) 2014-07-09 2016-10-27 A method for treating movement disorders with befiradol
US16/717,019 US11090298B2 (en) 2014-07-09 2019-12-17 Method for treating movement disorders with befiradol
US17/359,182 US12472169B2 (en) 2014-07-09 2021-06-25 Method for treating movement disorders with befiradol

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018057576A1 (fr) 2016-09-22 2018-03-29 Auspex Pharmaceuticals, Inc. Composés de pyridin- et pyrimidin-2-yl-méthylamine substitués par du deutérium
WO2019016357A1 (fr) 2017-07-20 2019-01-24 Neurolixis Utilisation d'agonistes sélectifs des récepteurs 5-ht1a de la sérotonine pour traiter les effets indésirables des inhibiteurs du vmat

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10548885B2 (en) * 2014-07-09 2020-02-04 Pierre Fabre Medicament Method for treating movement disorders with befiradol

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6020345A (en) 1996-11-21 2000-02-01 Pierre Fabre Medicament Pyridin-2-yl-methylamine derivatives, method of preparing and application as medicine
US7208603B2 (en) 2001-02-09 2007-04-24 Pierre Fabre Medicament Synthesis method and intermediates of pyridin-2-yl-methylamine
WO2013004249A1 (fr) * 2011-07-05 2013-01-10 Concit Pharma Aps Utilisation d'agonistes de récepteur de sérotonine pour le traitement de troubles des mouvements
WO2013156035A1 (fr) * 2012-04-18 2013-10-24 Concit Pharma Aps Formulation pharmaceutique disponible pour une administration par voie orale appropriée pour une gestion améliorée de troubles du mouvement

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5431922A (en) * 1991-03-05 1995-07-11 Bristol-Myers Squibb Company Method for administration of buspirone
US6060345A (en) * 1997-04-21 2000-05-09 Advanced Micro Devices, Inc. Method of making NMOS and PMOS devices with reduced masking steps
MX2007001760A (es) 2004-08-12 2007-07-24 Quest Pharmaceutical Services Composiciones farmaceuticas para la distribucion de liberacion controlada de compuestos biologicamente activos.
US7040843B1 (en) 2005-03-17 2006-05-09 Great Lakes Custom Tool Mfg., Inc. Flooring hollow back relief cutting tool and method
GB2460915B (en) 2008-06-16 2011-05-25 Biovascular Inc Controlled release compositions of agents that reduce circulating levels of platelets and methods therefor
WO2011008546A2 (fr) 2009-06-29 2011-01-20 Capricorn Pharma, Inc. Formes posologiques solides ou semi-solides et systèmes et procédés de formation et de conditionnement de celles-ci
JP5699339B2 (ja) * 2010-02-12 2015-04-08 日産化学工業株式会社 徐放性製剤
US20120076865A1 (en) * 2010-03-24 2012-03-29 Jazz Pharmaceuticals, Inc. Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
WO2012030314A1 (fr) 2010-09-01 2012-03-08 Mithridion, Inc. Compositions comprenant de la 5-(3-éthyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tétrahydropyrimidine, et procédés d'administration desdites compositions
EP2627328B1 (fr) * 2010-10-15 2016-09-14 Contera Pharma APS Combinaisons d'agonistes de récepteurs de sérotonine pour le traitement de troubles du mouvement
WO2013156036A1 (fr) 2012-04-18 2013-10-24 Jesco Holding Aps Appareil d'enroulement pour enroulement d'un film sous la forme d'un rouleau
US10548885B2 (en) * 2014-07-09 2020-02-04 Pierre Fabre Medicament Method for treating movement disorders with befiradol
WO2025035048A1 (fr) 2023-08-09 2025-02-13 Via Separations, Inc. Appareil de filtration comprenant des membranes d'oxyde de graphène modifiées par des polymères

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6020345A (en) 1996-11-21 2000-02-01 Pierre Fabre Medicament Pyridin-2-yl-methylamine derivatives, method of preparing and application as medicine
US7208603B2 (en) 2001-02-09 2007-04-24 Pierre Fabre Medicament Synthesis method and intermediates of pyridin-2-yl-methylamine
WO2013004249A1 (fr) * 2011-07-05 2013-01-10 Concit Pharma Aps Utilisation d'agonistes de récepteur de sérotonine pour le traitement de troubles des mouvements
WO2013156035A1 (fr) * 2012-04-18 2013-10-24 Concit Pharma Aps Formulation pharmaceutique disponible pour une administration par voie orale appropriée pour une gestion améliorée de troubles du mouvement

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
COLPAERT ET AL., NEUROPHARMACOLOGY, vol. 43, 2002, pages 945 - 958
REMINGTON: "The science and Practice of Pharmacy", 2006, MACK PUBLISHING COMPANY
ROPPONGI ET AL., PROG NEUROPSYCHOPHARMACOL BIOL PSYCHIATRY, vol. 31, no. 1, 2007, pages 308 - 310
ROPPONGI ET AL., PROG NEUROPSYCHOPHARMACOL BIOL PSYCHIATRY, vol. 31, no. 1, 2007, pages 308 - 310 0
SHIMIZU ET AL., AGING AND DISEASE, vol. 4, no. 1, 2013, pages 1 - 13
VENN: "Principles and Practice of Bioanalysis", 2008, CRC PRESS
WISE: "Handbook of Pharmaceutical Controlled Release", 2000, MARCEL DEKKER PUBLISHING COMPANY

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018057576A1 (fr) 2016-09-22 2018-03-29 Auspex Pharmaceuticals, Inc. Composés de pyridin- et pyrimidin-2-yl-méthylamine substitués par du deutérium
US10626105B2 (en) 2016-09-22 2020-04-21 Auspex Pharmaceuticals, Inc. Deuterium-substituted pyridin- and pyrimidin-2-yl-methylamine compounds
WO2019016357A1 (fr) 2017-07-20 2019-01-24 Neurolixis Utilisation d'agonistes sélectifs des récepteurs 5-ht1a de la sérotonine pour traiter les effets indésirables des inhibiteurs du vmat
US11191758B2 (en) 2017-07-20 2021-12-07 Neurolixis Use of selective serotonin 5-HT1A receptor agonists for treating side-effects of VMAT inhibitors

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